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FOUNDATIONS 3 COURSE: INTRODUCTION TO DIAGNOSIS, DETECTION AND THERAPY (DDT) Course Competencies based on OU College of Medicine Educational Objectives: 1. Patient Care Students will demonstrate: • The essential of formulating a problem list and differential diagnosis. • The ability to interpret results of commonly used diagnostic studies. • The ability to reason deductively in solving clinical problems. • The ability to communicate effectively, both orally and in writing. • Awareness of health promotion and disease prevention. 2. Medical Knowledge Students will demonstrate: • Knowledge of the normal structure and function of the immune system and the function of its cellular components. • Knowledge of the molecular, biochemical and cellular mechanisms that is important in maintaining the body’s homeostasis. • Knowledge of the various causes and pathogenesis of maladies, emphasizing the common and important clinical, laboratory, radiologic and pathologic manifestations. • Knowledge of the pathology and pathophysiology of the body and its major organ systems that are seen in various diseases and conditions. • Understanding of the power of the scientific method in establishing the causation of disease and efficacy of tradition and non-traditional therapies. • The skills of lifelong learning. We will have an active learning experience in this course on immune suppression or a similar topic. 3. Experience-based learning and Improvement Students will demonstrate: • The ability to retrieve, effectively evaluate and use medical literature to provide evidence based practice. (depends on delivery methods used) 4. Interpersonal and Communication Skills • The ability to work effectively with others as a member of a health care team or other professional group in an active learning environment to be decided later. 5. Professionalism • As a group decide on behaviors that contribute to professionalism. 6. Systems-Based Practice – not applicable to this course. D. Specific Learning Objectives Immunology • • • • • Describe the components of the innate immune system (organs, cell and major cytokines) and the complement system. Include the mechanisms that contribute to eradication of disease. Describe the components (organs, cells and major cytokines) of the adaptive immune response and the mechanisms the use to contribute to eradication of disease. Describe the structure of the five classes of immunoglobulin and the unique role for each in the immune response. Describe the nature of antigens including the characteristics of antigens that contribute to their immunogenicity. Include the meaning of the terms antigen determinant, epitope and hapten. Discuss procedures to produce antibodies including the role that route of exposure and adjuvants play. Include a description of the difference in polyclonal antibodies and monoclonal antibodies. • • • • • • • • • • • • • List the immunological assays that are commonly used in clinical laboratories to assist in the diagnosis of disease. Include their use and relative sensitivity. Describe the cellular a molecular events that activate cells of the humoral immune system including the mechanisms responsible for isotype switching and somatic hyper-mutation. Describe the effector mechanisms utilized by the humoral immune response including the participation of the complement system. Describe the structure of lymphocyte antigen receptors and how immune repertoires are generated. Describe the molecules encoded by the major histocompatibility complex and how they contribute to induction of cell-mediated immune responses including the mechanism of antigen processing. Describe the cellular and molecular mechanisms used for activation of T lymphocytes including which receptors, adhesions, co-stimulatory molecules and major cytokines are involved. Describe the effector mechanisms utilized by the cell-mediated immune system. List the mechanisms used for maintaining self-tolerance by the immune system, including mechanisms for central tolerance and peripheral tolerance in T- and B- lymphocytes. List the roles that genetics and infectious disease may play in the generation of autoimmune diseases. Describe the basic mechanisms of damage resulting in representative autoimmune diseases. Describe how the immune response can participate in the rejection of malignant tumors and how tumors may evade the immune response. Describe the role of the MHC and the immune system in rejection of foreign grafts including methods used in clinical medicine to reduce the impact of these mechanisms. Describe the four types of hypersensitivity states, the mechanisms of responsible for tissue for each type and examples of clinical syndromes that are a result of each type of hypersensitivity. Describe the immunodeficiency diseases that are caused by defects in granulocyte function, T-cell function, Bcell function or those resulting in severe combined immune deficiency. Where known indicate the major phenotypic and genotypic cause of the immunodeficiency state. Inflammation • List the primary cell types that are involved in acute and chronic inflammation and briefly discuss their role in the inflammatory reaction to tissue injury • List the five classical signs and symptoms of acute inflammation and discuss the underlying events that lead to each • Describe in sequence the series of events that comprise the acute inflammatory response and the mechanisms by which they occur • Describe the steps involved in the isolation and destruction of an infectious agent by polymorphonuclear leukocytes • Discuss the source(s) and the role(s) that chemical mediators play in acute inflammation • Compare and contrast the different patterns of inflammation (serous, catarrhal, fibrinous, hemorrhagic, suppurative, ulcerative, gangrenous, and pseudomembranous) in terms of etiology, morphologic appearance, and clinical significance • Describe the systemic effects of acute and chronic inflammation and briefly discuss the underlying mechanisms that produce those effects. • Discuss the role of the clinical laboratory in diagnosing acute inflammation in terms of expected laboratory findings • Compare and contrast non-specific chronic inflammation and granulomatous inflammation in terms of etiology, morphologic appearance, clinical implication, and outcome Wound Healing • List the potential outcomes of tissue injury • Describe the cell cycle and define the single-lettered abbreviations (M, G0, G1, S, G2) • Compare and contrast the properties of labile, stable, and permanent cells and give examples of each • Describe three stimuli that might initiate cellular replication • Discuss the basic aspects of collagen synthesis and function • Be aware of the major types of collagen and their differing properties • Describe in sequence the series of events that lead to the formation of scar tissue and discuss the underlying mechanisms by which those events occur • • • • • • • • • • • • Discuss the role of chemical mediators in the healing process Compare healing by first intention (primary union) and second intention (secondary union) in terms of time, sequence of events, morphologic changes, and final outcome List the major factors that can interfere with wound healing List two aberrant outcomes that may occur during wound healing and discuss the underlying mechanisms of each Discuss the structure and physiologic maintenance of normal bone Describe the three phases of bone repair Discuss the significance of an adequate vascular supply to healing bone List three major factors that can ensure rapid repair of a bone fracture Discuss the factors that significantly delay or prevent normal bone healing Discuss drug-induced allergic and pseudoallergic reactions (likelihood of specific drugs causing reactions, clinical presentation, treatment). List major immunosuppressant agents, their major clinical uses, major and unique ADRs, and significant interactions of each. List peptide and proteins which are used as drugs, the major clinical use of each, pharmacokinetic and allergic considerations of each, major and unique ADRs, and significant interactions of each. Microbiology • Describe the cell wall of Gram-positive and Gram-negative bacterial cell wall and the function of the layers of the cell wall. • Describe the structure of teichoic and lipoteichoic acids in the bacterial cell wall and the function of these structures. • Describe how the outermembrane of the Gram-negative bacterial cell differs from the cytoplasmic membrane. • Describe the structure of the lipopolysaccharide of the Gram-negative cell and why it is important to the pathogenesis of the organism. • Describe the functions of bacterial nucleoid, pili, flagella, sex pili, axial filaments and spores. • Describe the differences in prokaryotic and eukaryotic cell structures. • Describe the Gram-stain characteristic along with the various cellular shapes and cell grouping that aid in the identification of bacteria. • Discuss the genetic processes that allow genes encoding virulence traits and antibiotic resistance to pass from one bacterial cell to another. • Describe the various types of conditions where bacterial can grow • Discuss the bacterial growth cycle including the definitions for the lag, lag, stationary and death phases of growth. • Describe the agents that can be used for disinfection, antisepsis, sterilization and sanitation as they relate to bacterial contamination. • Describe the mechanism of action of the major classes of anti-bacterial, anti-fungal and anti-viral agents currently used in clinical medicine. • Define the terms specific toxicity, bacteriostatic, bacteriocidal, and therapeutic index. • Describe the characteristics of fungal organisms that are used in the identification of these eukaryotic cells. • Describe the structure of the various classes of viral pathogens and their replication schemes. Understand the difference between these agents and prions. • Become familiar with some of the basic mechanisms of pathogenesis used by bacterial, viral and eukaryotic pathogens. • To become familiar with the common methods used for diagnosis of bacterial, fungal and viral infections with the goal of gaining an understanding of the methods are should be used for transport of specimens to the laboratory and how to interpret the results reported from the laboratory. Antimicrobial Drugs • List the factors that a clinician should follow to select an appropriate antimicrobial regimen. • List the important host factors that must be considered when choosing an antimicrobial regimen for a patient. • Describe the mechanism of action of the major classes of anti-bacterial, anti-fungal and anti-viral agents currently used in clinical medicine. • Define the terms specific toxicity, bacteriostatic, bactericidal, and therapeutic index. • • • • • • • • • • • Identify major drug-drug interactions for commonly prescribed anti-infectives. List common drug toxicities associated with specific antimicrobial agents. Explain the advantages and disadvantages of combination antimicrobial therapy. Discuss mechanisms of antimicrobial resistance. Discuss pharmacokinetic parameters of major drug classes. Discuss contraindications for particular drugs and drug classes. Discuss organisms targeted by specific drugs and drug classes. Discuss mechanism(s) of action for major drug classes. Discuss the treatment of tuberculosis infections. Review commonly used vaccines. Discuss treatment options for HIV infected patients. Neoplasia • Outline the classification and nomenclature for benign and malignant neoplasms • Apply the appropriate standard terminology to neoplastic growths according to the specific features of the neoplasm • Compare and contrast benign and malignant neoplasms in terms of cellular morphology, cellular differentiation, rate of growth, mode of growth, and potential to metastasize • List three major mechanisms of metastatic spread of malignant tumors • Discuss potential local and systemic effects resulting from the presence of a neoplastic mass • Discuss the role of chemical agents, ionizing radiation, and viral infection in the development of malignant neoplasms • List the functional traits that distinguish malignant cells from benign cells • Discuss the function of proto-oncogenes • Describe mechanisms of oncogene activation • Discuss the potential effects of oncogene activation on cell function • Compare and contrast the properties of oncogenes and tumor suppressor genes and give examples of both • Discuss the similarities and differences between inherited neoplasms and spontaneous neoplasms • Discuss the implications of germ line genetic mutations as opposed to somatic genetic mutations • Discuss the events that transform benign non-neoplastic cells into malignant neoplastic cells • Discuss factors that influence the growth of malignant neoplasms • Describe properties of malignant cells that enable metastatic spread • Discuss factors that can promote or impede metastatic spread of malignant neoplasms • Describe the methods of establishing tumor grade and tumor stage • Discuss the clinical significance of grading and staging of malignant neoplasms • Discuss the features of malignant neoplasms that influence the overall prognosis for the patient. • Discuss the possibility/validity of “preventative” treatment for patients with the genetic predisposition to cancer. Cancer Chemotherapy • Using the Gompertzian growth curve, define the following terms related to cancer growth: exponential tumor growth, growth fraction, tumor burden, and doubling time. • Distinguish among duration of survival, response rate, duration of response, toxicity, and quality of life as indicators of the usefulness of a specific cancer therapy. • Describe the role of tumor heterogeneity in the design of chemotherapy drug regimens. • Compare and contrast the use of leucovorin in conjunction with chemotherapy regimens containing fluorouracil versus its role in regimens containing methotrexate. • Given a class of cytotoxic drugs, describe toxicities that are common to the class and toxicities that are unique to specific drugs within that class. • Given patient-specific laboratory indicators of impaired liver and/or renal function, recommend dose modification for commonly used chemotherapy agents. • Describe at least three differences between cancerous and normal cells that have been successfully exploited in the development of biologically targeted anticancer agents. • Given two commonly used and related chemotherapy drugs, compare the therapeutic characteristics, such as mechanisms, toxicity pattens, administration issues, and common clinical uses. • • • • Given a list of monoclonal antibodies approved for cancer treatment, match the antibody with its mechanism, clinical use, and/or antigenic target. Given a category of serious toxicity produced by cytotoxic drugs, identify the drugs commonly associated with the toxicity, characteristic time course of the toxicity, pathophysiology of the toxicity, and risk factors for developing such toxicity. Given patient at risk of severe myelosuppression secondary to antineoplastic drugs, recommend appropriate use of hematopoietic growth factors. Given patient-specific information for a cancer patient with fever and neutropenia, recommend a plan for initial assessment and treatment. Autonomic Nervous System • List, in tabular form, characteristics of the somatic and autonomic nervous systems. • On a summary diagram of the autonomic and somatic nervous systems, label all of the parts of the diagram. Include the division of the nervous system, the neurotransmitters, and the receptors stimulated by the neurotransmitters. • Describe the anatomy, neurotransmitters, and receptors that are characteristic of the sympathetic nervous system. Identify the proportion of norepinephrine and epinephrine that is released from the adrenal medulla. • Describe the anatomy, neurotransmitters, and receptors that are characteristic of the parasympathetic nervous system. • List the classes of cholinergic receptors, and list the drugs that block each of these classes of receptors. • List the classes of adrenergic receptors. List examples of drugs that stimulate and block the alpha and beta receptors. • Describe the general rules that apply to the actions of adrenergic receptors. • Define “functional synergism,” and provide an example. • Define “tonic activity.” Explain the significance of tonic activity in the autonomic nervous system. • Describe the effects and receptors used by the two divisions of the autonomic nervous system for the following organ systems: eyes, cardiovascular system, lungs, gastrointestinal tract, bladder muscle, reproductive tract in the male, and sweat glands. • List, in order, the sequence of neural events that occurs in the baroreflex for either a decrease or an increase in blood pressure. • Describe the functions of the anatomical structures involved in the micturition reflex. List the relative activity levels (high or low) of each of these structures during continence (storage of urine) and voiding (micturition). • Describe five diseases that can result from autonomic nervous system dysfunction. General Principles of Pharmacology • Understand how the biochemical properties of a drug can affect its function. • Understand what a receptor is and how activation or inhibition of a receptor modulates cell physiology/pathology. • Be able to apply the terminology for quantifying receptor-mediated drug activities. • Understand the causes and mechanism of individual variability in drug response. • Understand and apply pharmacokinetic parameters. • Be able to design dosing regimens using the pharmacokinetic parameters. • Be able to identify the causes of and how to compensate for changes in a dosing regimen given changes in a patient’s condition. • Learn the types of biotransformation, where they occur, and the molecular mechanisms. • Understand how genetic factors can affect biotransformation. • Learn which environmental factors can affect biotransformation and how. • List the major drug laws and the gist of each law; classify drugs by controlled substance category and describe what these mean for the prescriber. • List the major Latin abbreviations, practical equivalents, and common practices used in prescribing medications. Clinical Toxicology • Use of emetics and activated charcoal in the general management of toxic exposures • Well established antidotes for specific drug/chemical exposure • Management of commonly encountered toxic exposures to selected drug classes (analgesics, cardiac drugs, stimulants, psychiatric drugs) • Management of toxic exposures to selected household or environmental toxicants (alcohols, poisonous gases, pesticides) • Chelating agents used in the management of heavy metal toxicology Tissue Injury • Discuss the structure and function of the cell nucleus, cytoplasmic organelles, and plasma membrane • Discuss potential causes of, identify the morphologic alteration created by, and discuss the significance of intracellular accumulations of water, lipids, glycogen, proteins, and pigments • Compare fatty change (steatosis) and fatty ingrowth on the basis of etiology, morphologic appearance and commonly involved organs • Compare carbon, lipofuscin, melanin, hemosiderin, and bilirubin in terms of color (in H&E stains), origin, clinical significance, and potential associated disorders • Understand the concept of using “special stains” ( stains other than the routine hematoxylin and eosin stains) on tissues • Discuss the similarities and differences between hemochromatosis and hemosiderosis • Discuss the differences between physiologic and pathologic cellular adaptations and give examples of physiologic and pathologic atrophy, hypertrophy, and hyperplasia • Define, list potential causes of, and discuss the significance of cellular atrophy, hypertrophy, aplasia, hypoplasia, hyperplasia, metaplasia, and dysplasia • List the alterations that can occur in cell injury with respect to the following cellular organelles: lysosomes, endoplasmic reticulum, mitochondria, and cytoskeleton • Compare the morphologic features associated with reversible cell injury to those associated with irreversible cell injury • Discuss the similarities and differences between ischemia, hypoxemia, and hypoxia • Discuss and give examples of factors that influence a cell’s sensitivity to hypoxia/anoxia • Discuss the sequence of events leading to irreversible cell injury due to anoxia/hypoxia • Discuss the sequence of events leading to irreversible cell injury due to free radical injury • Compare and contrast coagulative necrosis, gangrenous necrosis, liquifactive necrosis, caseous necrosis, enzymatic fat necrosis, traumatic fat necrosis, and fibrinoid necrosis in terms of potential causes, morphologic appearance (gross and microscopic), and clinical implications • Define and describe the two distinct pathways of caspase activation that leads to apoptosis • Give examples of pro-apoptotic factors and anti-apoptotic factors • Discuss the similarities and differences between apoptosis and necrosis • Discuss the effects of ionizing radiation in terms of molecular changes within a cell and the subsequent morphologic changes that may be expressed • Describe those characteristics that render some tissues more susceptible than others to the effects of ionizing radiation • Describe the potential long term clinical consequences of ionizing radiation • Compare and contrast localized and systemic hypothermia • Compare and contrast full thickness burns and partial thickness burns in terms of clinical significance • Discuss the potential acute complications of severe burns • Discuss mechanisms of injury resulting from electrical current and list factors that influence the extent of electrical injury • Discuss the effects of acute changes in atmospheric pressure on body tissues • Define and discuss mechanical injuries (abrasions, avulsions, contusions, lacerations, incisions, and punctures) in terms of etiology and gross morphologic appearance • Discuss, in general terms, mechanisms of injury due to exogenous chemicals and/or drugs • Compare and contrast dystrophic and metastatic calcifications in terms of pathogenesis and clinical significance Fluid Balance and hemodynamics • Describe the physiologic processes responsible for maintaining normal fluid balance • Describe the mechanisms by which the physiologic processes that maintain normal fluid balance may be altered, and discuss the clinical consequences of altering those processes • Compare and contrast intracellular and interstitial edema ,and discuss the clinical significance of each • Given a clinical situation, be able to discuss possible mechanisms underlying the development of interstitial edema • Compare and contrast transudate and exudate in terms of etiology, key features, and clinical significance • Compare and contrast vascular congestion and hyperemia in terms of mechanisms of development and clinical significance • Discuss the physiologic effects and resultant clinical signs and symptoms of left-sided heart failure • Discuss the physiologic effects and resultant clinical signs and symptoms of right-sided heart failure • Compare and contrast acute and chronic congestion in terms of etiology, morphologic effect on involved tissue, and clinical significance • List the major causes of chronic passive congestion of the lungs and describe its effects in terms of morphologic changes (gross and microscopic) and clinical signs and symptoms • List the major causes of chronic congestion of the liver and describe its effects in terms of morphologic changes (gross and microscopic) and clinical signs and symptoms • Describe the events occurring in and discuss the significance of anticoagulation • Describe the events occurring in and discuss the significance of thrombolysis • Discuss the prominent role of thrombin in blood homeostasis • Compare and contrast arterial thrombosis, venous thrombosis, and capillary thrombosis in terms of etiology, morphologic appearance, and potential sequelae • Discuss the similarities and differences between pale infarcts and hemorrhagic infarcts in terms of etiology and morphologic appearance • Discuss disseminated intravascular coagulation (DIC) in terms of etiology, signs and symptoms, and clinical significance • Compare and contrast arterial emboli and venous emboli in terms of clinical signs, symptoms, and outcome • List predisposing factors that may lead to pulmonary emboli • Describe the morphologic changes in the lung and the clinical signs and symptoms which may occur as the result of pulmonary emboli • Discuss the fat emboli syndrome in terms of etiology, clinical manifestations, and clinical outcomes • List five potential etiologies of shock • Discuss the underlying hemodynamic events that occur in patients in shock • Describe the potential morphologic changes of tissue that occur in patients in shock and discuss the clinical manifestations of those changes